Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints.

Osteoarthritis (OA) is a painful, incurable disease affecting over 500 million people. Recent clinical trials of the nerve growth factor (NGF) inhibitors in OA patients have suggested adverse effects of NGF inhibition on joint structure. Here we report that nerve growth factor receptor (NGFR) is upregulated in skeletal cells during OA and plays an essential role in the remodeling and repair of osteoarthritic joints. Specifically, NGFR is expressed in osteochondral cells but not in skeletal progenitor cells and induced by TNFα to attenuate NF-κB activation, maintaining proper BMP-SMAD1 signaling and suppressing RANKL expression in mice. NGFR deficiency hyper-activates NF-κB in murine osteoarthritic joints, which impairs bone formation and enhances bone resorption as exemplified by a reduction in subchondral bone and osteophytes. In human OA cartilage, NGFR is also negatively associated with NF-κB activation. Together, this study suggests a role of NGFR in limiting inflammation for repair of diseased skeletal tissues.

Functions and Metabolism of Amino Acids in Bones and Joints of Cats and Dogs.

The bone is a large and complex organ (12-15% of body weight) consisting of specialized connective tissues (bone matrix and bone marrow), whereas joints are composed of cartilage, tendons, ligaments, synovial joint capsules and membranes, and a synovial joint cavity filled with synovial fluid. Maintaining healthy bones and joints is a dynamic and complex process, as bone deposition (formation of new bone materials) and resorption (breakdown of the bone matrix to release calcium and phosphorus) are the continuous processes to determine bone balance. Bones are required for locomotion, protection of internal organs, and have endocrine functions to maintain mineral homeostasis. Joints are responsible for resisting mechanical stress/trauma, aiding in locomotion, and supporting the overall musculoskeletal system. Amino acids have multiple regulatory, compositional, metabolic, and functional roles in maintaining the health of bones and joints. Their disorders are prevalent in mammals and significantly reduce the quality of life. These abnormalities in companion animals, specifically cats and dogs, commonly lead to elective euthanasia due to the poor quality of life. Multiple disorders of bones and joints result from genetic predisposition and are heritable, but other factors such as nutrition, growth rate, trauma, and physical activity affect how the disorder manifests. Treatments for cats and dogs are primarily to slow the progression of these disorders and assist in pain management. Therapeutic supplements such as Cosequin and formulated diets rich in amino acids are used commonly as treatments for companion animals to reduce pain and slow the progression of those diseases. Also, amino acids (e.g., taurine, arginine, glycine, proline, and 4-hydroxyproline), and glucosamine reduce inflammation and pain in animals with bone and joint disorders. Gaining insight into how amino acids function in maintaining bone and joint health can aid in developing preventative diets and therapeutic supplementations of amino acids to improve the quality of life in companion animals.

Shape variation and sex differences of the adult human mandible evaluated by geometric morphometrics.

In cases of osseous defects, knowledge of the anatomy, and its age and sex-related variations, is essential for reconstruction of normal morphology. Here, we aimed at creating a 3D atlas of the human mandible in an adult sample using dense landmarking and geometric morphometrics. We segmented 50 male and 50 female mandibular surfaces from CBCT images (age range: 18.9-73.7 years). Nine fixed landmarks and 510 sliding semilandmarks were digitized on the mandibular surface, and then slid by minimizing bending energy against the average shape. Principal component analysis extracted the main patterns of shape variation. Sexes were compared with permutation tests and allometry was assessed by regressing on the log of the centroid size. Almost 49 percent of shape variation was described by the first three principal components. Shape variation was related to width, height and length proportions, variation of the angle between ramus and corpus, height of the coronoid process and inclination of the symphysis. Significant sex differences were detected, both in size and shape. Males were larger than females, had a higher ramus, more pronounced gonial angle, larger inter-gonial width, and more distinct antegonial notch. Accuracy of sexing based on the first two principal components in form space was 91 percent. The degree of edentulism was weakly related to mandibular shape. Age effects were not significant. The resulting atlas provides a dense description of mandibular form that can be used clinically as a guide for planning surgical reconstruction.

Computational modelling of articular joints with biphasic cartilage: recent advances, challenges and opportunities.

Biphasic models have been widely used to simulate the time-dependent biomechanical response of soft tissues. Modelling techniques of joints with biphasic weight-bearing soft tissues have been markedly improved over the last decade, enhancing our understanding of the function, degenerative mechanism and outcomes of interventions of joints. This paper reviews the recent advances, challenges and opportunities in computational models of joints with biphasic weight-bearing soft tissues. The review begins with an introduction of the function and degeneration of joints from a biomechanical aspect. Different constitutive models of articular cartilage, in particular biphasic materials, are illustrated in the context of the study of contact mechanics in joints. Approaches, advances and major findings of biphasic models of the hip and knee are presented, followed by a discussion of the challenges awaiting to be addressed, including the convergence issue, high computational cost and inadequate validation. Finally, opportunities and clinical insights in the areas of subject-specific modeling and tissue engineering are provided and discussed.

Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1.

Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the "ligand-free" CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.

Dihydroartemisinin alleviates erosive bone destruction by modifying local Treg cells in inflamed joints: A novel role in the treatment of rheumatoid arthritis.

Treg cell-based therapy has exhibited promising efficacy in combatting rheumatoid arthritis (RA). Dihydroartemisinin (DHA) exerts broad immunomodulatory effects across various diseases, with its recent spotlight on T-cell regulation in autoimmune conditions. The modulation of DHA on Treg cells and its therapeutic role in RA has yet to be fully elucidated. This study seeks to unveil the influence of DHA on Treg cells in RA and furnish innovative substantiation for the potential of DHA to ameliorate RA. To this end, we initially scrutinized the impact of DHA-modulated Treg cells on osteoclast (OC) formation in vitro using Treg cell-bone marrow-derived monocyte (BMM) coculture systems. Subsequently, employing the collagen-induced arthritis (CIA) rat model, we validated the efficacy of DHA and probed its influence on Treg cells in the spleen and popliteal lymph nodes (PLN). Finally, leveraging deep proteomic analysis with data-independent acquisition (DIA) and parallel accumulation-serial fragmentation (PASEF) technology, we found the alterations in the Treg cell proteome in PLN by proteomic analysis. Our findings indicate that DHA augmented suppressive Treg cells, thereby impeding OC formation in vitro. Consistently, DHA mitigated erosive joint destruction and osteoclastogenesis by replenishing splenic and joint-draining lymph node Treg cells in CIA rats. Notably, DHA induced alterations in the Treg cell proteome in PLN, manifesting distinct upregulation of alloantigen Col2a1 (Type II collagen alfa 1 chain) and CD8a (T-cell surface glycoprotein CD8 alpha chain) in Treg cells, signifying DHA's targeted modulation of Treg cells, rendering them more adept at sustaining immune tolerance and impeding bone erosion. These results unveil a novel facet of DHA in the treatment of RA.

Prepared for landing: A simple activation strategy scales muscle force to landing height.

Before landing from a jump or fall, animals preactivate muscles to stiffen their limb joints but it is unclear how muscles tune limb stiffness and how collision forcefulness is anticipated. We measured electromyography and force from the lateral gastrocnemius muscle during landings in turkeys, an animal model that allows for direct measurements of muscle force. Many studies of landings in humans and other animals have found the duration of muscle preactivation to be constant, starting approximately 100 ms before impact, irrespective of fall duration. Therefore, we hypothesized a lack of relationship between fall duration (as dictated by drop height), muscle activity onset-time, and force at toe-down. Contrary to our expectations, both muscle activity and force rose from briefly after fall initiation until toe-down. Preactivation duration was proportional to fall height, while the rate of force rise was consistent across drop heights, resulting in force at landing and leg stiffness being proportional to fall height. Onset of muscle activity lagged 22 ± 7 ms (mean ± S.E.M.) from fall initiation, consistent with a reflex response initiation of the force ramp-up. Together, our results suggest that a constant (clock-like) rate of motor unit recruitment, initiated at fall initiation provides a preactivation that is proportional to drop height. The result is a tuning of pre-landing muscle force, providing a limb stiffening that is proportional to impact intensity, possibly without using information about fall distance.

Evaluation of generic EMG-Torque models across two Upper-Limb joints.

Advanced single-use dynamic EMG-torque models require burdensome subject-specific calibration contractions and have historically been assumed to produce lower error than generic models (i.e., models that are identical across subjects and muscles). To investigate this assumption, we studied generic one degree of freedom (DoF) models derived from the ensemble median of subject-specific models, evaluated across subject, DoF and joint. We used elbow (N = 64) and hand-wrist (N = 9) datasets. Subject-specific elbow models performed statistically better [5.79 ± 1.89 %MVT (maximum voluntary torque) error] than generic elbow models (6.21 ± 1.85 %MVT error). However, there were no statistical differences between subject-specific vs. generic models within each hand-wrist DoF. Next, we evaluated generic models across joints. The best hand-wrist generic model had errors of 6.29 ± 1.85 %MVT when applied to the elbow. The elbow generic model had errors of 7.04 ± 2.29 %MVT when applied to the hand-wrist. The generic elbow model was statistically better in both joints, compared to the generic hand-wrist model. Finally, we tested Butterworth filter models (a simpler generic model), finding no statistical differences between optimum Butterworth and subject-specific models. Overall, generic models simplified EMG-torque training without substantive performance degradation and provided the possibility of transfer learning between joints.

Articular surface interactions distinguish dinosaurian locomotor joint poses.

Our knowledge of vertebrate functional evolution depends on inferences about joint function in extinct taxa. Without rigorous criteria for evaluating joint articulation, however, such analyses risk misleading reconstructions of vertebrate animal motion. Here we propose an approach for synthesizing raycast-based measurements of 3-D articular overlap, symmetry, and congruence into a quantitative "articulation score" for any non-interpenetrating six-degree-of-freedom joint configuration. We apply our methodology to bicondylar hindlimb joints of two extant dinosaurs (guineafowl, emu) and, through comparison with in vivo kinematics, find that locomotor joint poses consistently have high articulation scores. We then exploit this relationship to constrain reconstruction of a pedal walking stride cycle for the extinct dinosaur Deinonychus antirrhopus, demonstrating the utility of our approach. As joint articulation is investigated in more living animals, the framework we establish here can be expanded to accommodate additional joints and clades, facilitating improved understanding of vertebrate animal motion and its evolution.

Evaluation of the efficacy and safety of a herbal formulation for rheumatoid arthritis - A non-inferiority randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a diverse disease characterized by a variable, progressive course of articular and extra-articular symptoms that are linked with pain, disability, and mortality. The exact cause of rheumatoid arthritis is still being investigated, and there is no cure for this debilitating, persistent, painful disease. Qurs-e-Mafasil, a herbal Unani preparation, is regarded as a potent treatment for Waja'al-Mafasil, a condition clinically similar to rheumatoid arthritis, but scientific evidence is scarce. AIM OF THE STUDY: This study aimed to assess the non-inferiority of Qurs-e-Mafasil compared to celecoxib in the treatment of patients with rheumatoid arthritis. MATERIALS AND METHODS: This randomized controlled trial was conducted on seventy patients diagnosed with rheumatoid arthritis between the ages of 35 and 55 years. The participants were randomly allocated in a ratio of 3:2, with 42 participants in the test group and 28 participants in the control group. The test group was administered 2 tablets (each having 500 mg) of Qurs-e-Mafasil, while the control group was administered 1 capsule of Celecoxib 100 mg. Both medications were delivered for four weeks. The primary outcome measure was European League Against Rheumatism (EULAR) response criteria based on Disease Activity Score-28 (DAS28) assessed before and after therapy, whereas the secondary outcome measure was the change in joint pain severity as determined by a 100 mm Visual Analog Scale (VAS) at baseline and each follow-up. The safety of the interventions was evaluated based on adverse event monitoring at each follow-up and laboratory tests including hemogram, Liver Function Tests (LFTs), Kidney Function Tests (KFTs), and a complete urine examination performed at baseline and after four weeks of treatment. RESULTS: The per-protocol analysis was done on 50 participants (30 in test group and 20 in control group) who completed the study duration. Thus, at the conclusion of the trial, participants in the test and control groups had either a moderate or no response based on EULAR response criteria. The odds ratio for no response versus moderate response between the test and the control groups was 0.71 (95% CI: 0.20-2.55) with p = 0.744. Moreover, the observed mean differences in VAS scores between the test and the control groups at 1st, 2nd, 3rd, and final follow-up were -0.33 (95% CI: -6.65 to 5.99, p = 0.916), 0.50 (95% CI: -5.63 to 6.63, p = 0.870), 2.42 (95% CI: -2.95 to 7.78, p = 0.370), and 3.00 (95% CI: -1.82 to 7.84, p = 0.219), respectively. CONCLUSIONS: The differences in primary and secondary outcomes between the two groups indicate that Qurs-e-Mafasil, a herbal Unani formulation containing Zingiber officinale Roscoe rhizome, Colchicum luteum Baker root, Piper nigrum L. fruit, and Withania somnifera (L.) Dunal. root, is comparable to celecoxib in the treatment of rheumatoid arthritis.

Conventional video recordings dependably quantify whole-body lifting strategy using the Stoop-Squat-Index: A methods comparison against motion capture and a reliability study.

Whole-body lifting strategies could be derived from conventional video recordings using the Stoop-Squat-Index, which quantifies the ratio between trunk forward lean and lower extremity joint flexion from 0 (full squat) to 100 (full stoop). The purpose of this study was to compare Stoop-Squat-Indices derived from conventional video recordings to those from a three-dimensional marker-based motion capture system and to evaluate interrater and intrarater reliability of the video-based approach. Thirty healthy participants lifted a 5-kg box under different conditions (freestyle, squat, stoop). Kinematic data were recorded using a Vicon motion capture system (serving as reference standard) and an iPad camera. Stoop-Squat-Indices over the entire lifting cycle were derived separately from both approaches. Agreement was assessed using mean differences (video minus motion capture) and limits of agreement. Reliability was investigated by calculating intraclass correlation coefficients (ICC) and minimal detectable changes (MDC) over the course of the lifting cycle. Systematic errors were identified with Statistical Parametric Mapping-based T-tests. Systematic errors between the video-based and the motion capture-based approach were observed among all conditions. Mean differences in Stoop-Squat-Indices over the lifting cycle ranged from -6.9 to 3.2 (freestyle), from -1.8 to 5.3 (squat) and from -2.8 to -1.1 (stoop). Limits of agreement were lower when the box was close to the floor, and higher towards upright standing. Reliability of the video-based approach was excellent for most of the lifting cycle, with ICC above 0.995 and MDC below 3.5. These findings support using a video-based assessment of Stoop-Squat-Indices to quantify whole-body lifting strategy in field.

Electromyography-driven musculoskeletal models with time-varying fatigue dynamics improve lumbosacral joint moments during lifting.

Muscle fatigue is prevalent across different aspects of daily life. Tracking muscle fatigue is useful to understand muscle overuse and possible risk of injury leading to musculoskeletal disorders. Current fatigue models are not suitable for real-world settings as they are either validated using simulations or non-functional tasks. Moreover, models that capture the changes to muscle activity due to fatigue either assume a linear relationship between muscle activity and muscle force or utilize a simple muscle model. Personalised electromygraphy (EMG)-driven musculoskeletal models (pEMS) offer person-specific approaches to model muscle and joint kinetics during a wide repertoire of daily life tasks. These models utilize EMG, thus capturing central fatigue-dependent changes in multi-muscle bio-electrical activity. However, the peripheral muscle force decay is missing in these models. Thus, we studied the influence of fatigue on a large scale pEMS of the trunk. Eleven healthy participants performed functional asymmetric lifting task. Average peak body-weight normalized lumbosacral moments (BW-LM) were estimated to be 2.55 ± 0.26 Nm/kg by reference inverse dynamics. After complete exhaustion of the lower back, the pEMS overestimated the peak BW-LM by 0.64 ± 0.37 Nm/kg. Then, we developed a time-varying muscle force decay model resulting in a time-varying pEMS (t-pEMS). This reduced the difference between BW-LM estimated by the t-pEMS and reference to 0.49 ± 0.14 Nm/kg. We also showed that five fatiguing contractions are sufficient to calibrate the t-pEMS. Thus, this study presents a person and muscle specific model to track fatigue during functional tasks.

Factors associated with intervertebral cage subsidence in posterior lumbar fusion.

BACKGROUND: The interbody fusion apparatus is a key component of the operation and plays a key role in the postoperative efficacy. Cage subsidence is one of the common complications after lumbar fusion and internal fixation. Clinical studies on the risk factors of cage subsidence are incomplete and inaccurate, especially paravertebral muscle atrophy and intervertebral bone fusion time. METHODS: Among the patients who underwent PLIF surgery in our hospital from January 2016 to January 2019, 30 patients with cage subsidence and 30 patients without cage subsidence were randomly selected to be included in this study. The differences between the two groups were compared, and the relevant factors of cage subsidence were explored by single factor comparison and multiple logistic regression analysis. RESULTS: Bone mineral density (T) of the subsidence group [(- 1.84 ± 1.81) g/cm2 vs (- 0.87 ± 1.63) g/cm2, P = 0.018] was significantly lower than that of the normal group. There were 4 patients with end plate injury in the subsidence group (P = 0.038). Preoperative end plate Modic changes [I/II/III, (7/2/2) vs (2/5/8), P = 0.043] were significantly different between the two groups. In the subsidence group, preoperative rCSA of psoas major muscle [(1.43 ± 0.40) vs (1.64 ± 0.41), P = 0.043], CSA of paravertebral muscle [(4530.25 ± 776.55) mm2 vs (4964.75 ± 888.48) mm2, P = 0.047], paravertebral muscle rCSA [(3.03 ± 0.72) vs (3.84 ± 0.73), P < 0.001] and paravertebral muscle rFCSA [(2.29 ± 0.60) vs (2.89 ± 0.66), P < 0.001] were significantly lower than those in normal group. In the subsidence group, the vertebral body area [(1547.81 ± 309.89) mm2 vs (1326.48 ± 297.21) mm2, P = 0.004], the height of the immediately corrected vertebral space [(2.86 ± 1.10) mm vs (1.65 ± 1.02) mm, P = 0.020], immediately SL corrective Angle [(5.81 + 4.71)° vs (3.24 + 3.57) °, P = 0.009), postoperative PI-LL [(11.69 + 6.99)° vs (6.66 + 9.62) °, P = 0.029] and intervertebral fusion time [(5.38 ± 1.85) months vs (4.30 ± 1.49) months, P = 0.023] were significantly higher than those in the normal group. Multivariate logistic regression analysis showed that the time of intervertebral fusion (OR = 1.158, P = 0.045), the height of immediate intervertebral space correction (OR = 1.438, P = 0.038), and the Angle of immediate SL correction (OR = 1.101, P = 0.019) were the risk factors for cage subsidence. Bone mineral density (OR = 0.544, P = 0.016) and preoperative paravertebral muscle rFCSA (OR = 0.525, P = 0.048) were protective factors. CONCLUSION: Intervertebral fusion time, correctable height of intervertebral space, excessive Angle of immediate SL correction, bone mineral density and preoperative paravertebral muscle rFCSA are risk factors for cage subsidence after PLIF.

Intra-articular Fibrolipoma of the Stifle in a Dog.

A 12 yr old male castrated miniature Australian shepherd dog presented for surgical consultation of historical bilateral medial patellar luxations with a 3 mo history of an acute onset of a left pelvic limb lameness. Physical examination confirmed medial patellar luxations and a mass effect of the left stifle medially. Radiographs showed medial distension of the joint capsule by a soft tissue opacity. Fine-needle aspirate of the left stifle revealed a mesenchymal cell population. Left medial parapatellar stifle arthrotomy found a fatty mass, which was excised at its base. A benign fibrolipoma was diagnosed on histopathology, and the excision was expected to be curative. The owners reported immediate improvement of perceived comfort postoperatively. At 2 and 24 wk, the dog returned to a normal level of function. Lipomas of the stifle, although rare, should be considered as a differential for intra-articular masses causing lameness.

A post hoc comparative real-world analysis of HEAD-US score for joint health assessment of patients with severe haemophilia A and B in Spain.

AIM: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. METHODS: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. RESULTS: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p < .01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. CONCLUSION: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.

No correlation found between palpation and ultrasound for evaluation of effusion in the medial femorotibial and femoropatellar joint compartments of horses.

OBJECTIVE: To compare palpation and ultrasound scores of effusion of the medial femorotibial and femoropatellar joints of horses. ANIMALS: 40 horses (80 stifles) were evaluated over a 12-week period. METHODS: Horses > 1 year of age without history of stifle disease were enrolled from September to December 2022. Palpation of right and left medial femorotibial and femoropatellar joint compartments was performed. Amount of effusion was scored by a board-certified large animal surgeon, a third-year large animal surgery resident, and an equine sports medicine intern. Effusion of right and left medial femorotibial and femoropatellar joints was quantified with ultrasound by a board-certified equine sports medicine and rehabilitation clinician. Amount of effusion on palpation and ultrasound was graded as none-mild (1), moderate (2), or severe (3). A 2-way intraclass correlation coefficient evaluated interrater reliability of palpation scores. The Spearman rank correlation determined association between palpation and ultrasound scores. RESULTS: Interrater reliability for palpation of effusion was poor between all observers for all joint compartments. No significant correlation was identified between palpation and ultrasound scores for any joint compartment for any observer. CLINICAL RELEVANCE: Clinicians often rely on palpation of joint effusion as an indication of stifle pathology. We found interrater reliability to be poor for palpation scores, indicating low agreement for palpation of joint effusion between clinicians within our group. No correlation was found between palpation and ultrasound scores for joint effusion, indicating that clinicians should not rely on palpation alone to quantify joint effusion of the medial femorotibial and femoropatellar joints.

Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals.

Repeating patterns of synovial joints are a highly conserved feature of articulated digits, with variations in joint number and location resulting in diverse digit morphologies and limb functions across the tetrapod clade. During the development of the amniote limb, joints form iteratively within the growing digit ray, as a population of distal progenitors alternately specifies joint and phalanx cell fates to segment the digit into distinct elements. While numerous molecular pathways have been implicated in this fate choice, it remains unclear how they give rise to a repeating pattern. Here, using single-cell RNA sequencing and spatial gene expression profiling, we investigate the transcriptional dynamics of interphalangeal joint specification in vivo. Combined with mathematical modeling, we predict that interactions within the BMP signaling pathway-between the ligand GDF5, the inhibitor NOGGIN, and the intracellular effector pSMAD-result in a self-organizing Turing system that forms periodic joint patterns. Our model is able to recapitulate the spatiotemporal gene expression dynamics observed in vivo, as well as phenocopy digit malformations caused by BMP pathway perturbations. By contrasting in silico simulations with in vivo morphometrics of two morphologically distinct digits, we show how changes in signaling parameters and growth dynamics can result in variations in the size and number of phalanges. Together, our results reveal a self-organizing mechanism that underpins amniote digit segmentation and its evolvability and, more broadly, illustrate how Turing systems based on a single molecular pathway may generate complex repetitive patterns in a wide variety of organisms.

[Arthralgia in psoriasis vulgaris - sometimes it's worth taking a second look]. / Arthralgien bei Psoriasis vulgaris ­ manchmal lohnt ein zweiter Blick.

HISTORY AND CLINICAL FINDINGS: The 71-year-old patient reported long-standing inflammatory arthralgia due to psoriasis vulgaris. Therapy with methotrexate led to elevated liver values; the symptoms persisted under treatment with the TNFα inhibitor adalimumab. MEDICAL EXAMINATIONS: Using arthrosonography and MRI, a predominantly periarticular inflammatory pattern on the wrists, metacarpophalangeal joints and proximal interphalangeal joints could be objectified without post-inflammatory stigmata of psoriatic arthritis. Laboratory diagnostics revealed an elevated anti-HCV titer with a high viral load consistent with a florid hepatitis C. DIAGNOSIS: A predominantly extrahepatic hepatitis C with associated periarthritis was diagnosed. THERAPY AND COURSE: With combined, interferon-free antiviral therapy, arthralgia suspended completely. CONCLUSION: Hepatitis C can appear through extrahepatic manifestations in the form of periarticular inflammation. Suspicious inflammatory arthralgias in psoriasis vulgaris are not conterminous with the diagnosis of psoriatic arthritis and should be evaluated by a professional rheumatologist.